| Refinement of protein structure homology models via long, all-atommolecular dynamicssimulations. | |
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MedLine Citation:
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PMID: 22513870 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Accurate computational prediction of protein structure represents a longstanding challenge in molecular biology and structure-based drug design. Although homology modeling techniques are widely used toproduce low-resolution models, refining these modelsto high resolution has proven difficult. With long enough simulations and sufficiently accurate force fields, molecular dynamics (MD) simulations should in principle allowsuch refinement, but efforts to refine homology models using MD have for the most part yielded disappointing results. It has thus far been unclear whether MD-based refinement is limited primarily by accessible simulation timescales, force field accuracy, or both. Here we examineMD as a technique for homology model refinement using all-atom simulations, each at least 100 µs long-more than 100 times longer than previous refinement simulations-and a physics-based force field that was recently shown to successfully fold a structurally diverse set of fast-folding proteins. In MD simulations of24 proteins chosen from the refinement category of recent Critical Assessment of Structure Prediction (CASP) experiments, we find that in most cases,simulationsinitiated from homology models drift away from the native structure. Comparison with simulations initiated from the native structuresuggests that force field accuracy is the primary factor limitingMD-based refinement. This problem can be mitigatedto some extent by restricting sampling to the neighborhood of the initial model, leading to structural improvement that, while limited, is roughly comparable to the leading alternative methods. Proteins 2012. © 2012 Wiley Periodicals, Inc. |
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Authors:
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Alpan Raval; Stefano Piana; Michael P Eastwood; Ron O Dror; David E Shaw |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-19 |
Journal Detail:
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Title: Proteins Volume: - ISSN: 1097-0134 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-19 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8700181 Medline TA: Proteins Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Wiley Periodicals, Inc. |
Affiliation:
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D. E. Shaw Research, New York, NY 10036, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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